Hypochlorite-Mediated Fragmentation of Hyaluronan, Chondroitin Sulfates, and RelatedN-Acetyl Glycosamines: Evidence for Chloramide Intermediates, Free Radical Transfer Reactions, and Site-Specific Fragmentation
- 18 October 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 125 (45), 13719-13733
- https://doi.org/10.1021/ja0370591
Abstract
Myeloperoxidase released from activated phagocytes reacts with H2O2 in the presence of chloride ions to give hypochlorous acid. This oxidant has been implicated in the fragmentation of glycosaminoglycans, such as hyaluronan and chondroitin sulfates. In this study it is shown that reaction of HOCl with glycosaminoglycans and model compounds yields chloramides derived from the N-acetyl function of the glycosamine rings. The results of EPR spin trapping and product studies are consistent with the formation of amidyl radicals from these chloramides via both metal ion-dependent and -independent processes. In the case of glycosaminoglycan-derived amidyl radicals, evidence has been obtained in studies with model glycosides that these radicals undergo rapid intramolecular abstraction reactions to give carbon-centered radicals at C-2 on the N-acetyl glycosamine rings (via a 1,2-hydrogen atom shift) and at C-4 on the neighboring uronic acid residues (via 1,5-hydrogen atom shifts). The C-4 carbon-centered radicals, and analogous species derived from model glycosides, undergo pH-independent β-scission reactions that result in glycosidic bond cleavage. With N-acetyl glucosamine C-1 alkyl glycosides, product formation via this mechanism is near quantitative with respect to chloramide loss. Analogous reactions with the glycosaminoglycans result in selective fragmentation at disaccharide intervals, as evidenced by the formation of “ladders” on gels; this selectivity is less marked under atmospheric oxygen concentrations than under anoxic conditions, due to competing peroxyl radical reactions. As the extracellular matrix plays a key role in mediating cell adhesion, growth, activation, and signaling, such HOCl-mediated glycosaminoglycan fragmentation may play a key role in disease progression and resolution, with the resulting fragments modulating the magnitude and quality of the immune response in inflammatory conditions.Keywords
This publication has 49 references indexed in Scilit:
- Immunohistochemical Detection of Hypochlorite-Modified Proteins in Glomeruli of Human Membranous GlomerulonephritisLaboratory Investigation, 2002
- Cu(II) and Zn(II) complexes with hyaluronic acid and its sulphated derivative: Effect on the motility of vascular endothelial cellsJournal of Inorganic Biochemistry, 2000
- Hypochlorous Acid Disrupts the Adhesive Properties of Subendothelial MatrixFree Radical Biology & Medicine, 1997
- Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44.JCI Insight, 1996
- Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions.JCI Insight, 1994
- The Effect of Extracellular Matrix Molecules on the in Vitro Behavior of Bovine Endothelial CellsExperimental Cell Research, 1993
- Electron spin resonance studies of the reaction of hypochlorite with 5,5-dimethyl-1-pyrroline-N-oxideFree Radical Biology & Medicine, 1990
- Hyaluronan and type III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis.Thorax, 1989
- Rate Constants for Reactions of Inorganic Radicals in Aqueous SolutionJournal of Physical and Chemical Reference Data, 1988
- Hydroxyl radical-induced oxidation of diethyl ether in oxygenated aqueous solution. A product and pulse radiolysis studyThe Journal of Physical Chemistry, 1982